Integrins belong to a large family of α/β heterodimeric transmembrane proteins that are involved in cell adhesion to a wide variety of extracellular matrix proteins, cell-cell interactions, cell migration, proliferation, survival, and in maintenance of tissue integrity (Barczyk et al. Cell and Tissue Research 2010, 339, 269; Srichai, M. B.; Zent, R. in Cell-Extracellular Matrix Interactions in Cancer, 2010). In mammals, there are 24 α/β integrin heterodimers known from various combinations of 18 alpha and 8 beta subunits. Transforming Growth Factor-β (TGF-β) has a central role in driving a number of pathological processes underlying fibrosis, cell growth, and autoimmune diseases. Alpha V (αV) Integrins, that include αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, are involved in a critical pathway that leads to the conversion of latent TGF-β to its active form (Henderson, N. C.; Sheppard, D. Biochim, Biophys. Acta 2013, 1832, 891). Thus, antagonism of such αV integrin-mediated activation of latent TGF-β provides a viable therapeutic approach to intervene in TGF-β-driven pathological states (Sheppard, D. Eur. Resp. Rev. 2008, 17, 157; Goodman, S. L.; Picard, M. Trends Pharmacol. Sciences 2012, 33(7), 405; Hinz, B. Nature Medicine 2013, 19(12), 1567; Pozzi, A.; Zent, R. J. Am. Soc. Nephrol. 2013, 24(7), 1034). All five αV integrins belong to a small subset (8 out of 24) of integrins that recognize the Arginine-Glycine-Aspartic acid (RGD) motif present in their native ligands such as fibronectin, vitronectin, and Latency-Associated Peptide (LAP).
The expression of αV integrin subtypes varies significantly. For example, αVβ6 is expressed on epithelial cells at very low levels in healthy tissue but is significantly upregulated during inflammation and wound healing. αVβ3 and αVβ5 are expressed on osteoclasts, endothelial, smooth muscle, and solid tumor cells, as well as on pericytes and podocytes, while αVβ1 is expressed on activated fibroblasts and mesangial cells.
Common fibrotic conditions that represent major unmet medical needs are Idiopathic Pulmonary Fibrosis (IPF), liver and kidney fibrosis, Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Steato-Hepatitis (NASH), as well as systemic sclerosis. Two drugs, pirfenidone and nintedanib, that act by non-integrin-mediated mechanisms, have recently been approved for treatment of IPF. The present invention relates to compounds that inhibit or antagonize the action of one or more of the αV integrins in the treatment of pathological conditions, such as fibrosis and cancer, mediated by these integrins.
A number of selective or nonselective small molecule, peptidic, and antibody-based antagonists of αV integrins have been reported in the literature (Kapp, T. G. et al. Expert Opin. Ther. Patents 2013, 23(10), 1273; O'Day, S. et al. Brit. J. Cancer 2011, 105(3), 346; Pickarski, M. et al. Oncol. Rep. 2015, 33, 2737; Wirth, M. et al. Eur. Urol. 2014, 897; Henderson, N. C. et al. Nature Medicine 2012, 19(12), 1617; Horan, G. S. et al. Am. J. Resp. Crit. Care Med. 2008, 177, 56; Puthawala, K. et al. Am. J. Resp. Crit. Care Med. 2008, 177, 82; Reed, N. I. et al. Sci. Transl. Med. 2015, 7(288), 288ra79; Anderson, N. A. et al. WO 2014/154725 A1, WO 2016/046225 A1, WO 2016/046226 A1, WO 2016/046230 A1, WO 2016/046241 A1).